Project Summary Neuronal activity in the cerebral cortex underlies essential brain functions, including perception and cognition, and changes flexibly to adapt to changing behavioral states and environmental inputs. Several lines of evidence suggest that inhibitory interneurons, which use GABA as a neurotransmitter, may be key regulators of flexible cortical function. However, cortical GABAergic interneurons comprise several highly diverse subpopulations with complex interactions, and are differentially activated during behavioral states such as quiet wakefulness, locomotion, and arousal. This presents a challenge to identifying their precise roles. Interestingly, our preliminary data suggest that in the mouse visual cortex, interactions between two specific interneuron populations, those expressing the peptide somatostatin (SST-INs) and those expressing the vasoactive intestinal peptide (VIP-INs) dramatically affect behavioral state-dependent visual processing. This research will directly, using a cutting-edge, multi-level approach combining computational modeling and quantitative data analysis, two-photon laser scanning microscopy (2PLSM), and genetically targeted optogenetic manipulation of brain circuits in awake, behaving mice. We will causally test the links between the activity of defined cell populations during distinct behavioral states and sensory processing. We will address the following aims: (1) we will identify cell-type specific GABAergic interneuron contributions to sensory processing, (2) determine how behavioral state modulates the impact of GABAergic inhibition, (3) identify how distinct GABAergic interneuron populations regulate the correlational structure of visually evoked activity, and (4) determine how IN-IN interactions dynamically regulate visual tuning. Our results will generate unprecedented insight into the function of identified interneuron populations, discover fundamental computational motifs of visual function and dysfunction, and provide a tightly integrated computational/experimental foundation for Dr. Ferguson's long-term research program. This research has the potential to provide novel insight into the role of GABAergic interneurons in the impairment of visual processing in neurological and psychiatric disease. The work described above will be carried out by Dr. Ferguson in the Department of Neuroscience at the Yale University School of Medicine, under the supervision of her mentor, Dr. Jessica Cardin, and collaborators Drs. Michael Higley and Brent Doiron. The proposal is carefully designed to broaden Dr. Ferguson's arsenal of technical skills, hone her scientific reasoning, and provide career development training to prepare her to become an Assistant Professor at the end of the K99 phase, and to apply for independent R01 funding at the end of the R00 phase. These goals will be achieved through Dr. Ferguson's plans, described in this application, to perform research; to meet frequently with her mentor, collaborators, and other members of the Yale faculty with research interests/technical skills relevant to these studies; and to attend scientific meetings.